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Pubertal attainment and Leydig cell function following pediatric hematopoietic stem cell transplantation: a three-decade longitudinal assessment
Cattoni, A., Nicolosi, M. L., Capitoli, G., Gadda, A., Molinari, S., Louka, S., Buonsante, A., Orlandi, S., Salierno, G., Bellani, I., et al
Frontiers in endocrinology. 2023;14:1292683
Abstract
INTRODUCTION Impaired testosterone secretion is a frequent sequela following hematopoietic stem cell transplantation (HSCT) in pediatrics, but long-term longitudinal trendlines of clinical and biochemical findings are still scanty. METHODS Monocentric, retrospective analysis. Male patients transplanted <18 years between 1992 and 2021, surviving ≥2 years after HSCT and showing, upon enrollment, clinical and biochemical signs consistent with pubertal onset and progression were included. Clinical and biochemical data collected every 6-12 months were recorded. RESULTS Of 130 patients enrolled, 56% were prepubertal, while 44% were peri-/postpubertal upon HSCT. Overall, 44% showed spontaneous progression into puberty and normal gonadal profile, while the remaining experienced pubertal arrest (1%), isolated increase of FSH (19%), compensated (23%) or overt (13%) hypergonadotropic hypogonadism. Post-pubertal testicular volume (TV) was statistically smaller among patients still pre-pubertal upon HSCT (p 0.049), whereas no differences were recorded in adult testosterone levels. LH and testosterone levels showed a specular trend between 20 and 30 years, as a progressive decrease in sexual steroids was associated with a compensatory increase of the luteinizing hormone. A variable degree of gonadal dysfunction was reported in 85%, 51%, 32% and 0% of patients following total body irradiation- (TBI), busulfan-, cyclophosphamide- and treosulfan-based regimens, respectively. TBI and busulfan cohorts were associated with the lowest probability of gonadal event-free course (p<0.0001), while it achieved 100% following treosulfan. A statistically greater gonadotoxicity was detected after busulfan than treosulfan (p 0.024). Chemo-only regimens were associated with statistically larger TV (p <0.001), higher testosterone (p 0.008) and lower gonadotropin levels (p <0.001) than TBI. Accordingly, the latter was associated with a 2-fold increase in the risk of gonadal failure compared to busulfan (OR 2.34, CI 1.08-8.40), whereas being pre-pubertal upon HSCT was associated with a reduced risk (OR 0.15, CI 0.08-0.30). CONCLUSIONS a) patients pre-pubertal upon HSCT showed a reduced risk of testicular endocrine dysfunction, despite smaller adult TV; b) patients showed downwards trend in testosterone levels after full pubertal attainment, despite a compensatory increase in LH; c) treosulfan was associated to a statistically lower occurrence of hypogonadism than busulfan, with a trend towards larger TV, higher testosterone levels and lower gonadotropins.
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Thyroid disorders following hematopoietic stem cell transplantation in childhood: the impact of the conditioning regimen on thyroid dysfunction, volume changes and occurrence of nodules
Cattoni, A., Molinari, S., Gaiero, A., De Lorenzo, P., Fichera, G., Riva, B., Di Marco, S., Tommesani, C., Mariani, E., Medici, F., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Thyroid late effects are among the most frequent sequelae reported after pediatric hematopoietic stem cell transplantation (HSCT). Though the detrimental effects of radiotherapy on the developing thyroid gland have been extensively assessed, the role of chemotherapy-only conditioning regimens is still controversial. OBJECTIVE We aimed at describing the occurrence, monitoring and management of thyroid function disorders (i.e. Graves' disease, Hashimoto thyroiditis and non-autoimmune hypothyroidism), nodules and volumetric changes over a 20-year observation period in a single pediatric transplant unit. In addition, we assessed the impact of different conditioning regimens on thyroid health. STUDY design Retrospective observational analysis. The study population included 244 patients transplanted for pediatric malignant or non-malignant diseases between 1999 and 2018 and for whom at least four thyroid function tests and one or more thyroid ultrasound(s) assessed sequentially after HSCT were available. RESULTS The 15-year cumulative incidence (CI) of either autoimmune or non-autoimmune thyroid dysfunctions (34%, SE 5.3%) did not statistically differ between total body irradiation- (TBI-) and chemo-based regimens (p 0.23). Indeed, the CI after busulfan (BU) was overall superimposable to that recorded after TBI (10-year CI: 22.2% versus 25.9%, respectively). Nevertheless, the CI of non-autoimmune hypothyroidism was statistically higher after BU- (12.4%, SE 3.7%) than after other chemotherapy only-based-conditionings (3.1%, SE 3.1%; p 0.02, 5-year CI), treosulfan included. The overall CI of nodules was low for the first 5 years after HSCT (1.9%, SE 0.9%), but it showed a subsequent steep increase over time, with a 15-year CI as high as 52.1% (SE 7.5%). TBI-conditioned patients experienced a higher 15-year CI of nodules (66.8%, SE 9.1%) compared to those receiving chemo-only regimens (33.6%, SE 9.5%; p 0.02), whereas age > 10 years upon transplantation showed a protective effect (HR 0.42, 95% confidence interval 0.2-0.88). Finally, a systematic sonographic follow-up highlighted a progressive statistically significant reduction in thyroid antero-posterior diameter among patients conditioned with TBI (p 0.005), but not after chemo-only regimens. CONCLUSIONS TBI and younger age upon HSCT play a remarkable and statistically demonstrated detrimental role on the occurrence of thyroid nodules, both benign and malignant. TBI and BU expose patients to a higher cumulative incidence of thyroid dysfunctions than other chemo-only regimens, treosulfan included. Accordingly, BU can be regarded as the most thyrotoxic agent among those administered as a part of a chemo-only conditioning regimen. Finally, patients conditioned with TBI, but not with other regimens, show a progressive decrease in thyroid volume over time, as assessed by sequential ultrasounds.
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Occurrence of long-term effects after hematopoietic stem cell transplantation in children affected by acute leukemia receiving either busulfan or total body irradiation: results of an AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) retrospective study
Saglio, F., Zecca, M., Pagliara, D., Giorgiani, G., Balduzzi, A., Calore, E., Favre, C., Faraci, M., Prete, A., Tambaro, F. P., et al
Bone marrow transplantation. 2020
Abstract
Patients given allogeneic hematopoietic stem cell transplantation (alloHSCT) present an increased incidence of long-term toxicities that can be attributed to the preparative regimen. We retrospectively analyzed in a population of 670 children receiving allo-HSCT for acute leukemia the occurrence of different late effects in function of the choice made between total body irradiation (TBI) and busulfan, as part of the preparative regimen. In univariable analysis, we found that patients treated with TBI developed cataract in 24% of the cases compared with 4% in patients treated with BU (p = 0.0001) and that the incidence of secondary malignant neoplasia (SMN) was higher in patients treated with TBI (18%) as compared with those prepared to the allograft with a Bu-based regimen (0%) (p = 0.019). Conditioning regimen did not show a statistically significant correlation with the occurrence of all the other investigated late effects. In multivariable analysis, TBI remained associated with the occurrence of cataracts (Relative Risk: 0.33 p = 0.012) and secondary malignancies (Relative Risk 3.96 x 10e-6 p < 0.001); however, other variables, as GvHD and disease type, were also correlated with these long-term sequels, indicating that in our study population the preparative regimen is not the only factor influencing the incidence of these complications.
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Guidance to bone morbidity in children and adolescents undergoing allogeneic hematopoietic stem cell transplantation
Kuhlen, M., Kunstreich, M., Niinimaki, R., Dunstheimer, D., Lawitschka, A., Bardit, E., Willasch, A., Bader, P., Hogler, W., Peters, C., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is widely performed in children and adolescents with hematologic diseases including very high-risk leukemia. With increasing success and survival rates, the long-term sequelae of HSCT have become important. Here, we provide guidance to the prevention and treatment of the most common bone morbidities - osteoporosis and osteonecrosis - emerging in the context of HSCT in children and adolescents. We give an overview on definitions, symptoms and diagnostics and propose an algorithm for clinical practice based on discussions within the International BFM SCT Committee and the Pediatric Disease Working Party of the European Society for Blood and Marrow Transplantation, our expert knowledge and a literature review.
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Hepatic focal nodular hyperplasia after pediatric hematopoietic stem cell transplantation: The impact of hormonal replacement therapy and iron overload
Cattoni, A., Rovelli, A., Prunotto, G., Bonanomi, S., Invernizzi, P., Perego, R., Mariani, A. M., Balduzzi, A.
Pediatric blood & cancer. 2019;:e28137
Abstract
BACKGROUND The advent of techniques for the assessment of iron overload (liver T2*-MRI) has led to the awareness that focal nodular hyperplasia (FNH) represents a possible incidental finding after hematopoietic stem cell transplantation (HSCT), though its pathogenesis is still unclear. METHODS We performed a retrospective analysis of the liver T2*-MRI scans performed between 2013 and 2018 in a single pediatric HSCT Unit and recorded the number of patients with FNH (group A). Patients incidentally diagnosed with FNH at imaging performed for different clinical indications were included in group B. RESULTS Nine of 105 (8.6%) patients from group A were diagnosed with FNH. Group B included three patients. Overall, 12 patients were diagnosed 4.4 +/- 3.1 years after HSCT. At univariate analysis, female gender (odds ratio [OR] 3.77, P = .03), moderate-to-severe iron overload (OR 6.97, P = .01), and hormone replacement therapy (HRT) administered for at least 6 months (OR 18.20, P = .0002) exposed patients to a higher risk of developing FNH. The detrimental effect of HRT was significant also at multivariate analysis (OR 7.93, P = .024). MRI-T2* values in affected patients were statistically lower than healthy controls (P < .001). CONCLUSIONS We confirm the high incidence of FNH among transplanted pediatric patients and demonstrate the potential pathogenic role of HRT and iron overload.